At present more than 200 different polyene macrolide antibiotics have been described, most of them being produced by soil actinomycetes, mainly by the genus Streptomyces.
Polyene macrolides (referred to in the following also as polyenes or macrolides) are characterized by 20- to 40-membered lactone rings containing three to eight conjugated carbon-carbon double bonds. Often, the lactone ring carries a sugar moiety. Some macrolides contain an aliphatic side chain, optionally carrying an aromatic substituent. Usually, the macrolide ring carries at least one hydroxyl group.
Nystatin was the first substance from the class of the polyene macrolides to be described. In 1961 it was isolated as the metabolite of the fungus species Streptomyces noursei. Nystatin, referred to in the following as Nys, has the following structural formula: ##STR1##
Due to its .pi.-electron structure comprising 4 conjugated double bonds, Nys is referred to as tetraene macrolide.
Another example of a polyene macrolide is Amphotericin B (referred to in the following as Amp). In contrast to Nys, this compound has an additional double bond. Since Amp exhibits a total of seven conjugated double bonds, it is classified among the group of the heptaene macrolides. Amp has the following structural formula: ##STR2##
Although particularly Nys and Amp have been known for several decades and have been administered orally to millions of patients, their therapeutical use has been limited exclusively to the treatment of candidiases (mycoses). In vitro studies have shown that Nys and Amp administered in decreasing dosages may have fungicidal, fungistatic or mycotic growth enhancing effect. Most scientific publications are quite silent about the latter effect. In turn, there are many in vivo studies which found cell-stimulating effects of Nys and Amp in eucaryotic cells (J. Bolard, How do polyene macrolide antibiotics affect the cellular membrane properties, Biochim. Biophys. Acta (1986), 864, 257-304).
It is assumed in the art that the antimycotic effect of Nys and Amp is based on a specific interaction with the membrane-bound ergosterol of the fungi. This interaction is believed to effect disruption of the fungal membranes, the entry of ions and other soluble substances in the fungi, thereby inhibiting the fungal metabolism and bringing about lysis of the fungal cells. It will be shown in the present invention that this conventional concept is not capable of explaining the manifold pharmacological effects of the polyene macrolides. The wrong pharmacodynamic concept, on which the practical use of this class of substances has so far been based, only can give an explanation for the fact that the universal therapeutical potential of polyene macrolides so far has not be recognized.
In the art, Nys and Amp are only used in the therapy of superficial and gastrointestinal mycotic infections. For example, for the treatment of intestinal candidiases and monoliases the administration of Nys in a dose of 3-4.times.10.sup.6 I.U./day over a period of 8 days, followed by a dose of 1.5 to 2.times.10.sup.6 I.U./day in the following 8 days is recommended. For the treatment of mycotic infections of the skin, e.g., application of a Nystatin cream (1.times.10.sup.5 I.U./g ointment) 2 to 3 times a day until remission of the infection (about 6 days) is recommended. 1 g Nys corresponds to about 5.times.10.sup.6 I.U. The oral and topical dosages, however, which are recommended in the art and are usually administered, are far lower and/or the duration of the treatment is considerably shorter than the dosage or duration of the therapy recommended by the present invention for the indications described in the invention. This may further explain why the new therapeutical effects of the polyene macrolides have not been recognized so far.
Additionally, there is the general assumption, which, however, is not verified by scientific findings, that polyene macrolides, such as Nys and Amp, are not or only insufficiently resorbed in the gastrointestinal tract upon oral, intranasal or topical administration (e.g., Van den Boussche, H. et al., CRC Crit. Rev. Microbiol. (1987), Vol. 15, 57-72; Arzneimittel Fortschritte 1972-1985, Kleeman et al. Eds., Verlag Chemie, Weinheim, Germany, 1176-1184; Goodman & Geiman's, The Pharmacological Basis of Therapeutics, (1992), 8.sup.th edition, Vol. 2, page 1178). This prejudice must be regarded as the main reason why the practical use of Nys has been limited to the local treatment of candidiases and why a possible systemic use has not been recognized.
There is yet another reason for the limited use of polyene macrolides in the art. It is known that Nys and all other polyenes are substantially toxic when administered intravenously or intramuscularly. Upon i.m. injection, severe local inflammations are observed. Upon i.v. administration, renal injuries as well as other severe side effects can occur. Therefore, Nys is not admitted for i.v. therapy. Amp, which is admitted for i.v. therapy, although it is even more toxic when administered in vitro and in vivo than Nys, may be administered only in doses that are 20- to 100-fold lower than the oral doses.
The practical experiences which were made world-wide with the oral therapy in millions of patients with Nys and Amp furthermore show that these substances are well-tolerated. Apart from a mild, temporary sickness in the beginning of the therapy, which occurs in less than 1% of patients and quickly abates, no severe side effects are so far known. This is evident from a literature search which evaluated about 2,000 publications dealing with this topic. This discrepancy--high toxicity upon i.v. and i.m. administration on the one hand and no toxicity upon oral administration on the other hand--has additionally reinforced the general prejudice that polyene macrolides are not resorbed.